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Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro

Authors
 Hyun-Young Park  ;  Hyuck Moon Kwon  ;  Hyun Joung Lim  ;  Bum Kee Hong  ;  Ju Yong Lee  ;  Byoung Eun Park  ;  Yang Soo Jang  ;  Seung Yun Cho  ;  Hyun-Seung Kim 
Citation
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.33(2) : 95-102, 2001 
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
 1226-3613 
Issue Date
2001
MeSH
Animals ; Arteriosclerosis/metabolism ; Blotting, Western ; Cell Division ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Growth Factors/metabolism ; Endothelium, Vascular/cytology* ; Endothelium, Vascular/enzymology* ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2/metabolism ; Immunohistochemistry ; Leptin/chemistry* ; Leptin/metabolism ; Leptin/physiology* ; Lymphokines/metabolism ; Matrix Metalloproteinases/biosynthesis* ; Neovascularization, Pathologic* ; Rats ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, Growth Factor/metabolism ; Receptors, Leptin ; Receptors, Vascular Endothelial Growth Factor ; Recombinant Proteins/metabolism ; Tissue Inhibitor of Metalloproteinases/metabolism ; Umbilical Veins/metabolism ; Up-Regulation ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors
Keywords
leptin ; angiogenesis ; MMPs ; atherosclerosis
Abstract
Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.
Files in This Item:
T200103667.pdf Download
DOI
10.1038/emm.2001.17
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Hyuck Moon(권혁문) ORCID logo https://orcid.org/0000-0001-9901-5015
Jang, Yang Soo(장양수) ORCID logo https://orcid.org/0000-0002-2169-3112
Hong, Bum Kee(홍범기) ORCID logo https://orcid.org/0000-0002-6456-0184
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/143051
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